It is well known to produce solid oral dosage forms of a type commonly referred to as sustained-release systems in which a pharmacologically active ingredient contained therein is released in a controlled manner in order to elicit the desired biological response. For instance, such formulations are used to provide delayed action of a drug for an interval of time or until it encounters certain physiological conditions. An example of the latter is a medication which is resistant to the acidic gastric juices but breaks down in the alkaline environment of the intestines with concomitant release of the active component.
Sustained-release properties of orally administered pharmaceutical compositions can be attained by means of diffusional systems in which the release rate of a drug is governed by its migration through a polymer membrane. There are two techniques whereby this can be effected. In one of these, a core of drug is encapsulated by a polymeric membrane. In the other technique and the one with which the invention is particularly concerned, the drug components are uniformly distributed throughout an inert polymeric matrix.
In preparing the matrix type of solid dosage forms, for example, granules, pellets and tablets, the wet granulation method is widely employed. The steps included are (1) weighing, (2) mixing, (2a) sieving, (2b) mixing, (3) granulation, (4) wet screening, (5) drying, (6) dry screening, (6a) addition of other desired ingredients, (7) lubrication and if tablets are desired, and (8) compression. Granules of the matrix containing drug are produced by wetting the powdered mass with a solution/suspension of the polymer followed by screening and drying of the wet granulation. After the drying step, the granulation is screened to the desired particle size.
The matrix containing a predetermined amount of polymer can be formed by adding to the dried powdered ingredients, a specific volume of a solution of the polymer in an organic solvent. A variation in such matrix formation, utilizes the polymer in the form of an aqueous dispersion. When carrying out the granulation, mixing of the liquid and solid component must be carefully controlled. The general rule of thumb is to add the liquid to the powdered mass until it takes on the consistency of damp snow or brown sugar. If the liquid component is an aqueous polymer dispersion, over wetting of the powdered mass may occur while attempting to deposit the desired weight of polymer. This will result in difficulties in the further processing of the over wetted granulation. On the other hand, insufficient wetting produces granules that are too soft, and generates excessive quantities of fines. This results in poor drug distribution and unsatisfactory flow and compression properties.
The trend to water based polymer systems is receiving increased attention owing to the implementation in recent years of stronger government safety regulations limiting solvent emissions from commercial chemical operations. The usual hazards, that is, toxicity and flammability are also associated with solvent use.
A class of aqueous polymer dispersions that are highly suitable in formulating pharmaceutical products are those in which the polymer particles are formed of at least one water-insoluble polymer of the type disclosed in U.S. Pat. No. 4,330,338 to Gilbert S. Banker. The aqueous polymer dispersions described therein are pseudolatices produced by dissolving the polymer in a water-immiscible solvent, forming an emulsion of the solvent solution in water and removing the water leaving very small particles of the polymer in the aqueous vehicle. Surfactants can be employed to facilitate emulsion formation.
The aqueous polymer dispersions of the cited patent were developed as coatings for solid pharmaceutical dosages and to this end were admixed with selected additives. These included annealing agents in the form of water-soluble polymers; emulsion stabilizers, particularly cetyl alcohol and n-decane; polishing agents, release agents, etc.
The water-insoluble polymer in the Banker aqueous dispersions can be of various types as exemplified by chemically modified, solvent soluble cellulose derivatives such as cellulose ethers and esters illustrative members of which are ethylcellulose and cellulose acetate phthalate. Other water-jnsoluble polymers may be used alone or added to the cellulosic polymer.
Although having wide application in formulating coating materials, the aqueous polymer dispersions of Banker are not readily amenable to the manufacture of pharmaceuticals by the wet granulation method. The main problem in this regard, is producing the Banker dispersions with sufficient polymer levels to provide matrix formation for sustained release without causing over wetting. Simply increasing the amount of polymer solvent solution to be emulsified in forming the pseudolatices is ineffective due to excessively high viscosities. Another possible approach is to use a more concentrated polymer solvent solution but this tends to promote formation of large polymer particles or clumps instead of a stable dispersion. Nor does raising polymer levels by removing some of the aqueous phase provide the answer since it leads to excessive foaming and unstable dispersions. Because of these deleterious effects, it is difficult to prepare Banker's dispersions in which the polymer content is much above about 30% by weight. At this level of polymer content, attendant over wetting would be a problem, particularly where the sustained-release composition produced from the dispersions contains a water-soluble drug substance and where the high ratio of the polymer to soluble drug is intended.